scholarly journals Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength

2013 ◽  
Vol 210 (4) ◽  
pp. 683-697 ◽  
Author(s):  
Inge Van de Walle ◽  
Els Waegemans ◽  
Jelle De Medts ◽  
Greet De Smet ◽  
Magda De Smedt ◽  
...  

In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor–ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ development. Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor–ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 2988-2998 ◽  
Author(s):  
Inge Van de Walle ◽  
Greet De Smet ◽  
Magda De Smedt ◽  
Bart Vandekerckhove ◽  
Georges Leclercq ◽  
...  

Abstract Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor αβ (TCR-αβ) versus TCR-γδ lineage decision is still unclear. Although it is clear in the mouse that TCR-γδ development is less Notch dependent compared with TCR-αβ differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and γδ T cells but inhibits differentiation toward the αβ lineage. Reducing the amount of Notch activation rescues αβ-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during αβ-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-γδ development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.


2001 ◽  
Vol 166 (1) ◽  
pp. 353-360 ◽  
Author(s):  
Atsushi Kumanogoh ◽  
Xiaosong Wang ◽  
Ihnsook Lee ◽  
Chie Watanabe ◽  
Masahito Kamanaka ◽  
...  

1997 ◽  
Vol 108 (1) ◽  
pp. 49-52 ◽  
Author(s):  
Binghe Wang ◽  
Hiroshi Fujisawa ◽  
Seiji Kondo ◽  
Gulnar G. Shivji ◽  
Danel N. Sauder

2014 ◽  
Vol 44 (5) ◽  
pp. 1320-1329 ◽  
Author(s):  
Annika Reinhardt ◽  
Sarina Ravens ◽  
Henrike Fleige ◽  
Jan D. Haas ◽  
Linda Oberdörfer ◽  
...  

2008 ◽  
Vol 22 (S2) ◽  
pp. 410-410
Author(s):  
Catherine Chih‐tzu Yin ◽  
Martin Felices ◽  
Yoko Kosaka ◽  
Joonsoo Kang

1999 ◽  
Vol 18 (10) ◽  
pp. 2793-2802 ◽  
Author(s):  
Bianca Blom ◽  
Mirjam H.M. Heemskerk ◽  
Martie C.M. Verschuren ◽  
Jacques J.M. van Dongen ◽  
Alexander P.A. Stegmann ◽  
...  

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1137-1144 ◽  
Author(s):  
Namita Saran ◽  
Marcin Łyszkiewicz ◽  
Jens Pommerencke ◽  
Katrin Witzlau ◽  
Ramin Vakilzadeh ◽  
...  

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.


2007 ◽  
Vol 215 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Sandra M. Hayes ◽  
Paul E. Love

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